Open chained or fused 1,1 &#39;-alkylene-bis-uracil derivatives, useful in skin uv-protection

ABSTRACT

The invention provides compounds of formula I; or a salt thereof as described herein. The invention also provides dermatological compositions comprising a compound of formula I or mixtures of one or more compounds of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods for protecting skin or DNA from photodamage or repairing photodamaged skin or DNA.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims the benefit of priority of U.S.application Ser. No. 61/713,355, filed Oct. 12, 2012, which applicationis herein incorporated by reference.

BACKGROUND OF THE INVENTION

Skin cancer is the most common cancer diagnosed in the United States andthe incidence of skin cancer continues to rise. Epidemiological studieshave documented that extensive sun exposure increases the risk ofdeveloping non-melanoma skin cancer. Photoprotection is the primarypreventative health strategy. Sunscreens are one of the most importantforms of photoprotection.

In general, the active ingredients in commercial sunscreens are mostlyaromatic hydrocarbons which absorb the light from ultraviolet radiation(UV) and degrade or generate very reactive intermediates via freeradicals. Such break down products which can be potentially harmful tothe skin (Free Radical Biology & Medicine 2006, 41, 1205-12). Severalrecent reports have suggested that current sunscreens may increasecancer risk (Int J. Environ. Res. Public Health 2007, 4(2), 126-31; FEBSLetters 1993, 324, 309-13).

Currently there is a need for additional agents or compostions that areuseful as sunscreens. There is also a need for agents or compositionscomprising said agents that act through unique mechanisms of action orthat are effective at lower concentrations or that produce non-toxicphotoproducts or less toxic photoproducts or lower concentrations ofphotoproducts. There is also a need for agents or compositionscomprising said agents that prevent or repair DNA damage in the skin orthat prevent or repair photo-damage to the skin.

SUMMARY OF THE INVENTION

The agents and compositions of the present invention have a uniquemechanism of action compared to existing agents and compositions (e.g.sunscreens) in the market. The agents of the present invention absorb UVlight and provide photo-protection to the skin. The resultingphoto-products initiate the body's natural defense mechanisms byincreasing cellular production of DNA repairing enzymes. Thus, theinvention provides compounds and compositions that have dual action ofproviding photo-protection and stimulating repair processes.

In one embodiment, the invention provides a compound of the inventionwhich is a compound of formula I:

wherein:

each R¹ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O; or the two R¹ groups together form a —(C₃-C₈)alkyl-group, a—(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl-group; or

the dashed bonds labeled “a” are absent and the dashed bonds labeled “b”are double bonds; or all the dashed bonds are single bonds;

R² is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R³ is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R⁴ is hydroxy, carboxy, (C₁-C₆)alkoxycarbonyl, —OPO₃H₂, —OR_(c), or—NR_(d)R_(e); and R⁵ is H; or R⁴ and R⁵ taken together are oxo;

Y is O, S, NH, P, P(═O) or POH;

Y′ is Si(R_(b))₂ or —Si(R_(b))₂—O—Si(R_(b))₂—;

-   -   each R_(a) is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or        aryl, wherein aryl is optionally substituted with one or more        (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

each R_(b) is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl,wherein aryl is optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups;

R_(c) is R_(f) or a C₁-C₂₀ saturated or C₂-C₂₀ unsaturated carbon chainthat is optionally substituted with one or more groups independentlyselected from oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, andaryl, wherein aryl is optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups;

R_(d) is H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl;

R_(e) is H or a C₁-C₂₀ saturated or C₂-C₂₀ unsaturated carbon chain thatis optionally substituted with one or more groups independently selectedfrom oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, and aryl, wherein aryl isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups;

each R_(f), is:

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR_(n1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen;

each R_(n1) is independently selected from H and (C₁-C₆)alkyl, whereinany (C₁-C₆)alkyl of R_(n1) is optionally substituted with one or more(e.g. 1, 2, 3, 4, 5 or 6) halogen;

each R_(p1) is independently (C₁-C₆)alkyl; and

R_(q1) and R_(r1) are each independently selected from H and(C₁-C₆)alkyl or R_(q1) and R_(r1) together with the nitrogen to whichthey are attached form a piperidine, pyrrolidine, morpholine, azetidine,thiomorpholine, piperazine or 4-methylpiperazine;

or a salt thereof.

The invention also provides a composition comprising a compound offormula I or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

The invention also provides a composition comprising a mixture of two ormore compounds of formula I, or pharmaceutically acceptable saltsthereof, and a pharmaceutically acceptable carrier.

The invention also provides a method for protecting mammal (e.g. human)skin from photo-damage comprising contacting the skin with one or morecompounds of formula I or pharmaceutically acceptable salts thereof.

The invention also provides a method for protecting DNA in mammal (e.g.human) skin from photo-damage comprising contacting the skin with one ormore compounds of formula I or pharmaceutically acceptable saltsthereof.

The invention also provides a method for repairing photo-damage inmammal (e.g. human) skin comprising contacting the skin with one or morecompounds of formula I or pharmaceutically acceptable salts thereof.

The invention also provides a method for stimulating DNA repair inmammal (e.g. human) skin comprising contacting the skin with one or morecompounds of formula I or pharmaceutically acceptable salts thereof.

The invention also provides a method for preventing skin cancer (e.g.basal cell carcinoma or squamous cell carcinoma) in a mammal (e.g. ahuman) or reducing the likelihood of contracting skin cancer (e.g. basalcell carcinoma or squamous cell carcinoma) in a mammal (e.g. a human)comprising contacting the skin with one or more compounds of formula Ior pharmaceutically acceptable salts thereof.

The invention also provides a method for reversing the signs of skinaging or preventing skin wrinkles in a mammal (e.g. a human) comprisingcontacting the skin with one or more compounds of formula I orpharmaceutically acceptable salts thereof.

The invention also provides a method for treating xeroderma pigmentosumin a mammal (e.g. a human) comprising contacting the skin with one ormore compounds of formula I or pharmaceutically acceptable saltsthereof.

The invention also provides a method for treating or preventing ionizingradiation damage in a mammal (e.g. a human) comprising treating themammal with one or more compounds of formula I or pharmaceuticallyacceptable salts thereof.

The invention also provides the use of one or more compounds of formulaI or pharmaceutically acceptable salts thereof, for the manufacture of amedicament useful for protecting mammal skin from photo-damage.

The invention also provides the use of one or more compounds of formulaI or pharmaceutically acceptable salts thereof, for the manufacture of amedicament useful for protecting DNA in mammal skin from photo-damage.

The invention also provides the use of one or more compounds of formulaI or pharmaceutically acceptable salts thereof, for the manufacture of amedicament useful for repairing photo-damage in mammal skin.

The invention also provides the use of one or more compounds of formulaI or pharmaceutically acceptable salts thereof, for the manufacture of amedicament useful for stimulating DNA repair in mammal skin.

The invention also provides the use of one or more compounds of formulaI or pharmaceutically acceptable salts thereof, for the manufacture of amedicament useful for preventing skin cancer (e.g. basal cell carcinomaor squamous cell carcinoma) or reducing the likelihood of developingskin cancer (e.g. basal cell carcinoma or squamous cell carcinoma) in amammal.

The invention also provides the use of one or more compounds of formulaI or pharmaceutically acceptable salts thereof, for the manufacture of amedicament useful for reversing the signs of skin aging or preventingskin wrinkles in a mammal.

The invention also provides the use of one or more compounds of formulaI or pharmaceutically acceptable salts thereof, for the manufacture of amedicament useful for treating xeroderma pigmentosum in a mammal.

The invention also provides the use of one or more compounds of formulaI or pharmaceutically acceptable salts thereof, for the manufacture of amedicament useful for treating or preventing ionizing radiation damagein a mammal.

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing compounds of formula I or salts thereof.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described.

The term “alkyl” as used herein refers to straight and branchedhydrocarbon groups. Reference to an individual radical such as propylembraces only the straight chain radical, a branched chain isomer suchas isopropyl being specifically referred to.

The term “halo” or “halogen” as used herein refers to fluoro, chloro,bromo and iodo.

The term “carbocycle” or “carbocyclyl” refers to a single saturated(i.e., cycloalkyl) or a single partially unsaturated (e.g.,cycloalkenyl, cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms(i.e. (C₃-C₇)carbocycle). The term “carbocycle” or “carbocyclyl” alsoincludes multiple condensed ring systems (e.g. ring systems comprising2, 3 or 4 carbocyclic rings). Accordingly, carbocycle includesmulticyclic carbocyles having 7 to 12 carbon atoms as a bicycle, and upto about 20 carbon atoms as a polycycle. Multicyclic carbocyles can beconnected to each other via a single carbon atom to form a spiroconnection (e.g. spiropentane, spiro[4,5]decane, spiro[4.5]decane, etc),via two adjacent carbon atoms to form a fused connection such as abicyclo[4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atomsarranged as a bicyclo[5,6] or [6,6] system (e.g. decahydronaphthalene,norsabinane, norcarane) or via two non-adjacent carbon atoms to form abridged connection (e.g. norbornane, bicyclo[2.2.2]octane, etc). The“carbocycle” or “carbocyclyl” may also be optionally substituted withone or more (e.g. 1, 2 or 3) oxo groups. Non-limiting examples ofmonocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl and cycloheptyl.

The term “aryl” as used herein refers to a single aromatic ring or amultiple condensed ring system. For example, an aryl group can have 6 to20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Arylincludes a phenyl radical. Aryl also includes multiple condensed ringsystems (e.g. ring systems comprising 2, 3 or 4 rings) having about 9 to20 carbon atoms in which at least one ring is aromatic. Such multiplecondensed ring systems may be optionally substituted with one or more(e.g. 1, 2 or 3) oxo groups on any carbocycle portion of the multiplecondensed ring system. It is to be understood that the point ofattachment of a multiple condensed ring system, as defined above, can beat any position of the ring system including an aryl or a carbocycleportion of the ring. Typical aryl groups include, but are not limitedto, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl,and the like.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase.

Specific values listed below for radicals, substituents, and ranges, arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents. Specificvalues listed are values for compounds of formula I as well as allsub-formulas of formula I (e.g. formulas Ia, and Ib).

A specific group of compounds of formula I are compounds of formula Ia:

and salts thereof.

A specific group of compounds of formula I are compounds of formula Ib:

and salts thereof.

A specific value for R¹ is independently H or (C₁-C₆)alkyl.

A specific value for Y is NH.

A specific value for R¹ is H.

Specifically R² and R³ can each independently be (C₁-C₆)alkyl.

A specific value for R⁴ is hydroxyl.

A specific value for R⁴ is carboxy.

A specific value for R⁴ is (C₁-C₆)alkoxycarbonyl.

A specific value for R⁴ is —OPO₃H₂.

A specific value for R⁴ is —OR_(c).

A specific value for R⁴ is —NR_(d)R_(e).

A specific value for R_(c) is a C₁-C₂₀ saturated or C₂-C₂₀ unsaturatedalkanoyl group that is optionally substituted with one or more groupsindependently selected from oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, andaryl.

A specific value for R_(c) is a C₁-C₂₀ saturated or C₂-C₂₀ unsaturatedalkanoyl group that is optionally substituted with one or more groupsindependently selected from oxo (═O), hydroxy, mercapto, carboxy, andaryl, and R_(f).

A specific value for R_(c) is R_(f).

A specific value for R_(c) is butanoyl, hexadecanoyl, octadecanoyl,benzoyl, 3-phenylprop-2-enoyl, or 3-(4-methoxyphenyl)prop-2-enoyl.

A specific value for R_(e) is H or a C₁-C₂₀ saturated or C₂-C₂₀unsaturated alkanoyl group that is optionally substituted with one ormore groups independently selected from oxo (═O), hydroxy, mercapto,(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e),carboxy, and aryl.

A specific value for R_(e) is a C₁-C₂₀ saturated or C₂-C₂₀ unsaturatedalkanoyl group that is optionally substituted with one or more groupsindependently selected from oxo (═O), hydroxy, mercapto, carboxy, andaryl, and R_(f).

A specific value for R_(e) is butanoyl, hexadecanoyl, octadecanoyl,benzoyl, 3-phenylprop-2-enoyl, or 3-(4-methoxyphenyl)prop-2-enoyl.

A specific compound is a compound which is selected from:

and salts thereof.

A specific compound is a compound which is selected from:

and salts thereof. Specific salts include salts withN,N-dimethylaminoethanol or glucosamine.

Processes for preparing compounds of formula I are provided as furtherembodiments of the invention and are illustrated in Schemes 1 and 2.

In cases where compounds are sufficiently basic or acidic, a salt of acompound of the formula can be useful as an intermediate for isolatingor purifying a compound of formula I. Additionally, administration of acompound of formula I as a pharmaceutically or dermatologicallyacceptable acid or base salt may be appropriate. Examples ofpharmaceutically acceptable salts including dermatologically acceptablesalts are organic acid addition salts formed with acids which form aphysiological acceptable anion, for example, tosylate, methanesulfonate,acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

Pharmaceutically acceptable salts which include dermatologicallyacceptable salts may be obtained using standard procedures well known inthe art, for example by reacting a sufficiently basic compound such asan amine with a suitable acid affording a physiologically acceptableanion. Alkali metal (for example, sodium, potassium or lithium) oralkaline earth metal (for example calcium) salts of carboxylic acids canalso be made.

The compounds of formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes. It is to be understoodthat the term pharmaceutically acceptable carrier also includes carriersthat are suitable for topical use as described herein below. In oneembodiment of the invention the pharmaceutically acceptable carrier is adermatologically acceptable carrier.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of bodyweight per day, such as 3 to about 50 mg per kilogram body weight of therecipient per day, preferably in the range of 6 to 90 mg/kg/day, mostpreferably in the range of 15 to 60 mg/kg/day.

The compound is conveniently formulated in unit dosage form; forexample, containing 5 to 1000 mg, conveniently 10 to 750 mg, mostconveniently, 50 to 500 mg of active ingredient per unit dosage form. Inone embodiment, the invention provides a composition comprising acompound of the invention formulated in such a unit dosage form.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The compounds of formula I can be formulated as dermatologicalcompositions and applied to a mammalian host, such as a human by atopical route. For topical administration, the present compounds may beapplied in pure form, i.e., when they are liquids. However, it willgenerally be desirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid carrier or a liquid carrier.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, cyclodextrins and the like.Useful liquid carriers include water, alcohols or glycols orwater-alcohol/glycol blends, in which the present compounds can bedissolved or dispersed at effective levels, optionally with the aid ofnon-toxic surfactants. Additional carriers include vegetable oils,hydrocarbon oils and waxes, silicone oils, animal and marine fats oroils. Adjuvants such as fragrances and additional antimicrobial agentscan be added to the composition to optimize the properties for a givenuse. Thickeners such as synthetic polymers, fatty acids, fatty acidsalts and esters, fatty alcohols, modified celluloses or modifiedmineral materials can also be employed with liquid carriers to formspreadable pastes, gels, ointments, soaps, and the like, for applicationdirectly to the skin of the user. Cosmetic compositions, may containconventional ingredients known to those of ordinary skill in the art,such as those described in Kirk-Othmer, Encyclopedia of ChemicalTechnology, Third Edition (1979), Vol. 7, pages 143-176. Specificingredients, including typical sunscreens, are listed in, for example,the above mentioned Kirk-Othmer Encyclopedia, at pages 153-154. Inaddition, topical preparations and cosmetic formulations may be preparedas described in U.S. Pat. Nos. 4,199,576, 4,136,165, and 4,248,861.Examples of additional useful dermatological compositions which can beused to deliver the compounds of the invention to the skin are known tothe art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392),Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157)and Wortzman (U.S. Pat. No. 4,820,508).

The percentage of the compositions and preparations may be varied. Ingeneral, a suitable dermatological composition will typically comprise acompound of formula I or a mixture thereof and may conveniently bebetween about 2-12% of the weight of a dermatological composition. Theamount of active compound in such dermatological useful compositions issuch that an effective level of compound will be obtained and/ormaintained for the desired duration of action.

Skin is the body's largest organ and is constantly under attack due toendogenous and exogenous factors. Amongst all the exogenous factors thatcause photo-damage to the skin, ultraviolet radiation plays an importantrole in damaging the integrity of the skin as demonstrated by variousstudies (Photochemisty and Photobiology 2002, 76, 561-69).

Sunscreens protect the DNA by reducing the absorption of sun'sultraviolet radiation to the epidermis. In the event of DNA damage, therepair mechanisms become essential for prevention against replicationerrors. DNA repair enzymes play a major role in reducing the DNAmalignancies.

The activity of the enzymes involved in the DNA damage repair is crucialfor over all genome integrity. The enzyme xpc is an important enzymeinvolved in the recognition and repair of DNA photoproducts in thenucleotide excision repair (NER) pathway. This particular enzyme (xpc)is also known to repair the DNA damage caused by the oxidative stressand UVA radiation [Mutation Research (2011) 728 (3) 107-117; The EMBOJournal (2006) 25, 4305-4315]. Our skin agents not only protect the DNAby absorbing UV light but also have shown to stimulate the essentialrepair enzyme, xpc involved in the first step of the DNA damage-repairsignaling cascade.

Upon absorption of UV from sun light, the chemical ingredients presentin commercial sunscreens can be broken down to form photo-products whichcan react with DNA to form cross links that are potentially toxic [Butt,S. T & Christensen, T; Toxicity and Phototoxicity of Chemical SunFilters: Radiat Prot Dosimetry (2000) 91 (1-3): 283-286]. There has beena continuous demand for safer and novel sunscreens that work by uniquemechanisms of action like and with the option of added benefits such asanti-aging and DNA repair enzyme stimulation.

The compounds of formula I and dermatological compositions thereof asdescribed above can be used in sunscreens or other cosmetic formulationsspecifically contemplated for the purpose of protecting skin or DNA inskin from photodamage or for repairing photodamaged skin or photodamagedDNA in the skin. It is apparent to those of ordinary skill in the artthat the compositions or formulations can be in many forms, including,but not limited to, for example, solutions, lotions, oils, sprays,creams, pastes, emulsions, sprays, or aerosols and delivered in asuitable manner.

Photodegradation is one of the factors for skin aging apart from thephysiological changes that occur in the skin. Skin aging slows down theproduction of some key components of extra-cellular matrix. The agentsof the present invention can not only help protect the skin from UVdamage but also initiate the cellular repair processes and therefore canalso be used to stimulate the production of key factors such ascollagen, elastin and hyaluronic acid involved in the skin agingprocesses.

In sunscreen or suntan lotion formulations it may be advantageous toinclude an effective amount of the compounds described in the presentinvention (e.g. one or more compounds of formula I) in combination withother conventional sunscreen agents. Other sunscreen agents include butare limited to avobenzone, ecamsule, methylanthranilate, oxybenzone,dioxybenzone and sulisobenzone, octinoxate, homosalate, octocrylene,octylsalate.

It has been determined that the compounds of formula I absorb UV lightat the same wavelength that DNA absorbs UV light. Upon exposure of UVlight a compound of formula Ia, Ic, or Ie is converted to acorresponding compound of formula Ib, Id or If respectively.Accordingly, the compounds of formula Ia, Ic or Ie may be useful toprotect DNA in the skin of a mammal (e.g. a human) from damage such asUV damage (e.g. UV-B) damage. In another embodiment of the invention thecompounds of formula Ia, Ic or Ie can protect skin from photodamage. Ithas also been discovered that compounds of formula Ia, Ic or Ie canstimulate DNA repair enzymes. Accordingly, in another embodiment thecompounds of formula Ia, Ic or Ie may be useful for the repair ofphotodamaged skin or for the repair of photodamaged DNA.

The exposure levels of ionizing radiation has grown significantly withthe use of tools like radiation therapy and X-rays. In addition,exposure can also occur at nuclear reactor sites. Exposure to radiationcan produce a variety of lesions in DNA including crosslinks andformation of dimers. Accordingly, effective anti-radiation drugs areurgently needed (e.g. drugs that can prevent or treat ionizing radiationdamage). Repair of damage to DNA is of central importance to all cellsand stimulation of these repair mechanisms may be useful anti-radiationtherapy. Certain compounds of the instant invention (e.g. compounds offormula Ia, Ic or Ie) are known to increase the cellular production ofDNA repairing enzymes. Accordingly, these compounds may have therapeuticutility for preventing or treating ionizing radiation damage in mammals.

The ability of a compound of the invention to protect DNA fromphotodamage may be determined using pharmacological models which arewell known to the art, or using Test A or Test B described below.

Test A. DNA Protection Assay (Solution)

Black tandem cuvettes were used in the following experiments. Blacktandem cuvettes (NSG Precision Cells Farmingdale, N.Y.; Cat#56UV10) arestandard 1 cm×3 cm cuvettes which have been divided into 2 chambers.Each chamber holds approximately 1.5 mL of liquid. All windows and thepartitions were polished and 3 sides were wrapped with black electricaltape leaving only one side for the UV light to go through and directingthe light through the protective solutions (OUTER CHAMBER) and then ontoinner solution (INNER SOLUTION).

DNA (100 μg pEGFP-C1 Plasmid DNA—Clontech/Takara) was placed in theINNER CHAMBER and protected by using 10 mM of our compound 16/18 ordegassed water in the OUTER CHAMBER. The tandem cuvettes were thenexposed to 1-300 nm UV bulbs in the Rayonet at 4° C. Aliquots (25 μL) ofthe DNA solution were taken at each time point (5, 10 or 15 minuteintervals). The irradiated DNA was digested with T4 endonuclease V, anenzyme specific for thymidine dimer damage. The DNA was incubated for 1hour at 37° C. in the presence of 20U (1 μL) T4 Endonuclease V and thenrun on a 1% Agarose gel (1×TBE, 0.5 hr at 50 V). The gel was thenstained with Ethidium bromide and visualized using a BioRad GelDocumentation System.

Test B. B. DNA Protection Assay (Cream)

A small amount of the cream (0.1 cc) was applied to the outside of blacktandem cuvettes and a quartz slide, cut to the size of the cuvette, wasplaced over the cream to make an even layer. The quartz cuvettes arewrapped in black electrical tape, leaving only one side for the UV lightto go through and directing the UV light through the protective cream.The DNA was irradiated using cream vehicle alone or compound 16/18 incream vehicle.

DNA (100 μg pEGFP-C1 Plasmid DNA—Clontech/Takara) was placed in theOUTER CHAMBER and protected by the cream applied to the outside of thecuvette. The tandem cuvettes were exposed to 1-300 nm UV bulbs in theRayonette at 4° C. Aliquots (25 μL) of the DNA solution were taken ateach time point (5, 10 or 15 minute intervals). The irritated DNA wasdigested with T4 endonuclease V, an enzyme specific for thymidine dimerdamage. The DNA was incubated for 1 hour at 37° C. in the presence of20U (1 μL) T4 Endonuclease V and then run on a 1% Agarose gel (1×TBE,0.5 hr at 50 V). The gel was stained with Ethidium bromide andvisualized using a BioRad Gel Documentation System.

The ability of a compound of the invention to protect DNA in cells maybe determined using pharmacological models which are well known to theart, or using Test C.

Test C. Cell Protection Assay (Cream)

RPMI-8226 cells (2.5×10⁶ cells/mL) were placed in 3 mL quartz blackcuvettes with a stir bar in the bottom of the cuvette to keep the cellsin uniform suspension during the experiment. The quartz cuvettes arewrapped in black electrical tape, leaving only one side for UV light togo through. A small amount of the cream (0.1 cc) was applied to theoutside of the black tandem cuvettes and a quartz slide, cut to the sizeof the cuvette, was placed over the cream to make an even layer and UVlight was directed through the protective cream. The cells were exposedto 1-300 nm UV bulb at 4° C. in the Rayonette with continuous stirringby a stir plate. At each time point, (15 and 30 minute intervals) acuvette containing cells was removed from the Rayonette. The cells wereprotected by using cream vehicle or AR compounds in cream vehicle.

Post exposure, the cells were transferred to sterile 1.7 mL tubes andthe cuvettes were washed with 1×500 μL, PBS and the contents weretransferred to the corresponding sterile 1.7 mL tube. The tubes werecentrifuged for 2 minutes at 13K rpm and 4° C., the supernatant wasdecanted and the cell pellets resuspended in Proteinase K. The tubeswere incubated for 3 hrs at 55° C. (to overnight) and the DNA wasisolated using the Isolation of DNA from Whole Cells Protocol. Theisolated DNA was digested with T4 endonuclease V, (1 hr, 37° C.) and runon a 1% Agarose gel (1×TBE, 1 hr at 50 V). The gel was stained withEthidium bromide and visualized using a BioRad Gel Documentation System.

The compounds that were examined in for tests A, B and C includingcompounds of the invention are shown in Table I. The compounds that weretested in tests A, B and C protected DNA from UV-induced damage forlonger periods of time when compared to controls. These resultsdemonstrate that compounds of the invention protect DNA fromphotodamage. Accordingly compounds of the invention may be useful asdermatological agents for the prevention of DNA damage in a variety offorms including sunscreens and cosmetics. (Compounds that were examinedin a test are denoted by an “X”)

in vitro assays in vivo plasmid DNA Mouse skin AR in water AR in creamAR in cream Compound # Test A Test B Test C 15 16 X X 17 X 18 X X X 20 X21 X 22 23 X 24 X

The ability of a compound of the invention to protect animal skin may bedetermined using pharmacological models which are well known to the art,or using Test D.

Test D. Murine Animal Studies

In accordance with IACUC Code Number: 0902A60149, 6-8 weeks old SKH-1were housed in RAR housing and did not receive any sunlight prior to thestudy. The UVA, UVB and Solar Simulated Light (SSL) treatment groupsincluded mice that were left untouched in their cages (no preventativetreatment) and mice treated topically on their backs with cream vehicleor AR compounds in the cream vehicle and rubbed with a glove. At 20minutes post treatment the mice were exposed to 180 mJ/cm² of UVA, UVBor SSL equivalent to one hour of noon day summer sunlight. One, four,eight and twenty-four hours post UVA, UVB or SSL exposure, the mice wereeuthanized by IP Ketamine/Xylazine injection and bled. The serum wascollected and sent to the Diagnostic Center for Population and AnimalHealth (DCPAH) at Michigan State University for 25-Hydroxyvitamin Danalysis and the Diagnostic Labs at the University ofMinnesota—Veterinary Medical Center for Small Animal Profile Panel.

The no UVA, UVB and SSL treatment groups included mice which were leftuntouched in their cages (no preventative treatment) and mice treatedtopically on their backs with cream vehicle and AR compounds in creamvehicle as indicated above. After treatment the mice were placed backinto their cages, away from sunlight. One, four, eight and twenty-fourhours post treatment, the no UVA, UVB and SSL treated mice wereeuthanized by IP Ketamine/Xylazine injection and bled. The serum wascollected and sent to the Diagnostic Center for Population and AnimalHealth (DCPAH) at Michigan State University for 25-Hydroxyvitamin Danalysis and the Diagnostic Labs at the University ofMinnesota—Veterinary Medical Center for Small Animal Liver and KidneyFunction Profile.

For the animal groups above, post euthanasia, the dorsal and belly skinwas collected and preserved in Zamboni's fixative for future studies.Skin samples are sent to the Masonic Cancer Center Comparative PathologyShared Resource at the University of Minnesota for H&E staining to lookfor skin irritation. The skin was analyzed in-house byimmunohistostaining (p53, thymine dimer, XPC and other DNA repairenzymes, collagen, elastin, etc.) and confocal microscopy.

Murine Animal Model Testing Results

Compound 17 (5% w/w based on acid) in cream vehicle was topicallyapplied topically to SKH-1 hairless mouse dorsal skin and exposed to UVBlight. Approximately 100 μl (0.1 cc) of each formulation was applied tomouse dorsal skin 20 minutes prior to UVB exposure. The treatment groupsreceived the standard dose of 6 KJ/m² and were harvested 4 hours afterirradiation. At harvest, dorsal skins were removed and fixed in zambonifixative. 5% (w/w based on acid) of compound 17 in cream vehicleprotected against thymine dimer formation as compared to the UV onlycontrol.

The ability of a compound of the invention to protect human skin may bedetermined using pharmacological models which are well known to the art,or using Test E.

Test E. Human Skin Study

Human skin was obtained from the University of Minnesota BioNet TissueProcurement Facility and stored on ice or in cell culture media untilready to be used. All samples were kept away from sunlight. The skin wascut into pieces and placed in 6-well cell culture plates with a smallamount of culture media at the bottom of the well but not enough tocover the top of the tissue. Using a gloved hand, the skin was rubbedwith cream vehicle or AR drug in the cream vehicle. At 20 minutes posttreatment the skin was exposed to 180 mJ/cm² of UVA, UVB or SolarSimulated Light (SSL) equivalent to one hour of noon day summersunlight. Post UVA, UVB or SSL exposure, additional media was placed inthe bottom of the wells and the plates moved to the tissue cultureincubator (37° C., 5% CO₂). Samples were removed from the incubator andplaced in Zamboni's fixative for future studies at one, four, eight andtwenty-four hours post UVA, UVB or SSL exposure.

Samples not exposed to UVA, UVB or SSL light were placed into 6-wellplates with a small amount of cell culture media but not enough to coverthe top of the tissue and stored in the cell culture incubator. The skinsamples not exposed to UVA, UVB or SSL light were treated with creamvehicle and AR in cream vehicle as indicated above. At 20 minutes posttreatment, the skin (in the plates) was moved into the cell cultureincubator (37° C., 5% CO₂). Samples were removed from the incubator andplaced in Zamboni's fixative for future studies at one, four, eight andtwenty-four hours post treatment.

All skin samples were analyzed in-house by immunohistostaining (p53,thymine dimer, XPC and other DNA repair enzymes, collagen, elastin,etc.) and confocal microscopy.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES

All chemicals were purchased from Sigma Chemicals, St. Louis, Mo. Allcompounds were characterized by 1H NMR, 13C NMR, mass and melting pointanalysis. Nuclear Magnetic Resonance spectra were recorded on a VarianXL 600 MHz instrument. All 1H and ¹³C NMR experiments are reported inunits, parts per million (ppm), and were measured relative to residualDMSO in the deuterated solvent. All coupling constants were reported inHz. Melting points were determined on Mel-Temp II apparatus and areuncorrected. Mass analyses were performed on Agilent LC-TOF 1100 massspectrometer equipped with either an ESI or APCI source.

Example 1 Preparation of Compounds 15 and 16

To a solution of O,O′-Bis(trimethylsilyl)-thymine (0.401 g, 1.482 mmol)in anhydrous DMF was added the dibromoester, 13 (0.255 g, 0.988 mmol) atRT and the reaction was heated to 75-80° C. The reaction mass wasevaporated to give an oily residue which was purified by SiO₂ flashchromatography to give the compound 14 (0.143 g, 64.7%) as an off whitesolid. ¹H NMR (600 MHz, DMSO-d⁶): δ 11.09 (s, 1H), 7.23 (s, 1H), 6.26(s, 1H), 5.52 (s, 1H), 4.01 (s, 2H), 3.43 (s, 3H), 1.85 (s, 3H); Mass(ESI-MS): 224.36 (M+).

To a solution of compound 14 (0.125 g, 0.558 mmol) in acetonitrile (30mL) was added the O,O′-Bis(trimethylsilyl)-thymine (0.181 g, 0.669 mmol)at RT and the reaction was stirred at RT. The reaction mass wasevaporated to give the crude solid which was purified by SiO₂ flashchromatography to give the compound 15 (0.139 g, 71.28%) as an off whitesolid. ¹H NMR (600 MHz, DMSO-d⁶): δ 11.25 (s, 2H), 7.46 (s, 2H), 3.83(d, 4H), 3.54 (s, 3H), 3.43 (m, 1H), 1.71 (s, 6H); ¹³C NMR (150 MHz,DMSO-d⁶): δ 174.12, 164.51, 151.35, 139.24, 53.11, 50.23, 40.34, 15.21,15.18; Mass (ESI-MS): 351.75 (M+H).

To a solution of compound 15 (0.113 g, 0.322 mmol) in water (10 mL) wasadded 1N NaOH (10 mL) at 0° C. and stirred carefully for 2-3 h. The pHof the reaction was adjusted to acidic (pH-2) and the precipitatedreaction mass was filtered, washed with dioxane-MeOH (1:1, 20 mL) anddried under vacuum to give the compound 16 (0.072 g, 66.71%) as a whitesolid. ¹H NMR (600 MHz, DMSO-d⁶): δ 12.81 (s. 1H), 11.24 (s, 2H), 7.44(s, 2H), 3.81 (d, 4H), 3.15 (m, 1H), 1.70 (s, 6H); ¹³C NMR (150 MHz,DMSO-d⁶): δ 179.25, 164.87, 152.33, 140.27, 51.47, 42.33, 16.22, 16.20;Mass (ESI-MS): 335.13 (M−H).

Example 2 Preparation of Salts 17 and 18

To a solution of the acid 16 (0.105 g, 0.312 mmol) in water (20 mL) wasslowly added N,N-dimethylaminoethanol (DMAE) (0.027 g, 0.312 mmol)) atRT. The contents were stirred for 1-2 h at RT. The solvent waslyophilized to give an amorphous solid which was washed with diethylether (25 mL) and dried under vacuum to give the DMAE salt of the acid17, as an off white powder. (0.125 g, 94%). ¹H NMR (600 MHz, DMSO-d⁶): δ10.76 (s, 2H), 7.16 (s, 2H), 3.71 (d, 4H), 3.42 (d, 2H), 3.01 (m, 1H),2.71 (d, 2H), 2.44 (s, 6H), 1.63 (s, 6H); Mass (ESI-MS): 335.46 (M−H)

To a solution of the acid 16 (0.125 g, 0.372 mmol)) in water (20 mL) wasslowly added glucosamine (0.066 g, 0.372 mmol) at RT. The contents werestirred for 1-2 h at RT. The solvent was lyophilized to give anamorphous solid and washed with diethyl ether (30 mL). The solids weredried under vacuum to give the glucosamine salt of the acid 18, as awhite powder (0.173 g, 90.57%). ¹H NMR (600 MHz, DMSO-d⁶): 11.12 (s,2H), 7.21 (s, 2H), 5.65 (d, 1H), 4.12-3.81 (m, 1H), 4.01-2.91 (m, 1H),3.73 (d, 4H), 3.66 (m, 1H), 3.45 (m, 1H), 1.71 (s, 6H); Mass (ESI-MS):335.87 (M−H).

Example 3 Preparation of Compound 21

To a solution of O,O′-Bis(trimethylsilyl)-thymine (1.186 g, 4.392 mmol)was added 3-chloro-(2-chloromethyl)prop-1-ene (0.252 g, 1.640 mmol), NaI(20 mG, 0.157 mmol) and potassium carbonate (0.559 g, 3.992 mmol) inanhydrous DMF (50 mL). The mixture was heated to 80° C. and stirredovernight. DMF was evaporated and the residue was purified by SiO₂ flashchromatography to give the compound 19 as a white solid (0.345 g,56.3%). ¹H NMR (600 MHz, DMSO-d⁶): 11.23 (s, 2H), 7.01 (s, 2H), 5.45 (s,1H), 5.21 (s, 1H), 5.65 (d, 1H), 3.81 (s, 4H); 1.75 (s, 6H); Mass(ESI-MS): 304.71 (M+).

Compound 19 (0.301 g, 0.99 mmol) was dissolved in a mixture of THF—H₂O(1:0.5 ratio; 30 mL). Sodium-periodate (1.059 g, 4.948 mmol) was addedin portion and stirred for 10 min at RT. Potassium osmate(VI) dihydrate(0.036 g, 0.099 mmol) was added to the reaction mass and stirredovernight at RT. The solvents were evaporated and methanol (10 mL) wasadded to dissolve the product and filtered. The filtrate were evaporatedand the residue was purified by SiO₂ flash chromatography to give thecompound 20 as a white solid (0.125 g, 41.31%). ¹H NMR (600 MHz,DMSO-d⁶): 11.12 (s, 2H), 6.31 (s, 2H), 4.13 (s, 4H), 1.81 (s, 6H); ¹³CNMR (150 MHz, DMSO-d⁶): δ 198.12, 163.34, 151.17, 140.57, 110.34, 55.73,15.23, 15.22; Mass (ESI-MS): 304.63 (M+); m.p: 320-331° C.

The compound 20 (0.158 g, 0.516 mmol) was suspended in H₂O (20 mL) andcooled to 0° C. Sodiumborohydride (0.191 g, 5.613 mmol) was carefullyadded to the reaction mixture in two portions. The reaction was stirredfor 2 h at 0° C. and slowly brought to RT. Methanol (10 mL) wascarefully introduced followed by the addition of H₂O (25 mL) toprecipitate the solids. The compound was recrystallized using a mixtureof water and ethanol (1:1) to give the compound 21 as a white solid(0.105 g, 66.03%). ¹H NMR (600 MHz, DMSO-d⁶): 11.01 (s, 2H), 6.45 (s,2H), 4.66-3.33 (m, 6H), 2.11 (s, 6H); ¹³C NMR (150 MHz, DMSO-d⁶): δ165.37, 150.43, 142.51, 111.57, 65.77, 1.23, 15.31, 15.28; Mass(ESI-MS): 308.71 (M+); m.p: 319-322° C.

Example 4 Preparation of Compound 22

A solution of 15 (0.052 g, 0.148 mmol) was dissolved in deionized water(100 mL, degassed) at 90° C., allowed to cool to room temperature in a500 mL Pyrex flask. A stream of nitrogen was bubbled throughout thecooling to room temperature. The solution was irradiated at 300 nm in aRayonet RPR 208 reactor and the reaction was monitored for theabsorption at 270 nm with a 50:1 aliquot test solution every 1 h untilreaction was complete (6 h). The irradiation was stopped and the roundbottom flask was ca. taken out of the reactor. The pH was adjusted to 9with aq.NaHCO₃. KMnO₄ (10 mg, 1.3 eqv) was added and stirred at roomtemperature for 4-5 h. Saturated aq. NaSH (10 mL) precipitated MnO₂which was removed by filtration. The carbonates in the filtrates weredecomposed by careful addition of formic acid. Concentration of thesolution to 30 mL furnished the photodimer as a crude product which wasrecrystallized from water to give the white solid 22 (0.025 g, 48.07%).¹H NMR (600 MHz, DMSO-d⁶): δ 10.35 (s, 2H), 4.01 (d, 2H), 3.76 (d, 4H),3.54 (s, 3H), 3.21 (m, 1H), 1.35 (s, 6H); ¹³C NMR (150 MHz, DMSO-d⁶): δ173.21, 161.15, 151.35, 57.13, 40.45, 15.33, 15.28; Mass (ESI-MS):351.25 (M+H).

Example 5 Preparation of Salts 23 and 24

A solution of DMAE salt of the acid, 17 (0.095 g, 0.223 mmol) wasdissolved in deionized water (100 mL, degassed) in a 500 mL Pyrex flask.A stream of nitrogen was bubbled throughout the cooling to roomtemperature. The solution was irradiated at 300 nm in a Rayonet RPR 208reactor and the reaction was monitored for the absorption at 270 nm witha 50:1 aliquot test solution every 1 h until reaction was complete (6h). The irradiation was stopped and the round bottom flask was ca. takenout of the reactor. The pH was adjusted to 9 with aq.NaHCO₃. KMnO₄ (10mg, 1.3 eqv) was added and stirred at room temperature for 4-5 h.Saturated aq. NaSH (10 mL) precipitated MnO₂ which was removed byfiltration. The carbonates in the filtrates were decomposed by carefuladdition of formic acid. Concentration of the solution to 30 mLfurnished the photodimer as a crude product which was recrystallizedfrom water to give the white solid 23 (0.054 g, 56.84%). ¹H NMR (600MHz, DMSO-d⁶): δ 10.22 (s, 2H), 4.22 (d, 2H), 3.97-3.86 (d, 4H), 3.76(d, 4H), 3.54 (s, 3H), 3.21 (m, 1H), 3.11 (m, 1H), 2.61 (d, 2H), 2.47(s, 6H), 1.31 (s, 6H); ¹³C NMR (150 MHz, DMSO-d⁶): δ 179.31, 161.60,153.54, 59.13, 65.12, 59.10, 58.64, 52.34, 47.25, 46.67, 41.45, 14.31,14.27; Mass (ESI-MS): 335.65 (M+H).

Compound 24 was prepared from the glucosamine salt of the acid (18) infollowing the procedure described for compound 23 in Scheme 9. ¹H NMR(600 MHz, DMSO-d⁶): δ 11.23 (s, 2H), 5.54 (d, 1H), 4.22-3.95 (m, 1H),4.11-3.01 (m, 1H), 3.43 (d, 4H), 3.76 (m, 1H), 3.55 (m, 1H), 1.71 (s,6H); ¹³C NMR (150 MHz, DMSO-d⁶): δ 178.35, 161.75, 152.34, 100.12,59.33, 71.23, 74.24, 66.21, 65.23, 63.15, 59.56, 58.34, 57.43, 52.71,47.35, 46.61, 41.51, 14.23, 14.19; Mass (ESI-MS): 335.55 (M+H).

Example 6

The following illustrate representative pharmaceutical dosage forms,containing a compound of formula I (‘Compound X’), for therapeutic orprophylactic use in humans.

(i) Tablet 1 mg/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0

(ii) Tablet 2 mg/tablet Compound X = 20.0 Microcrystalline cellulose410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0500.0

(iii) Capsule mg/capsule Compound X = 10.0 Colloidal silicon dioxide 1.5Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

(iv) Injection 1 (1 mg/ml) mg/ml Compound X = (free acid form) 1.0Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodiumchloride 4.5 1.0N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL

(v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 1.0N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL

(vi) Aerosol mg/can Compound X = 20.0 Oleic acid 10.0Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0Dichlorotetrafluoroethane 5,000.0

Example 7

The following illustrates a representative dermatological formulationcontaining a compound as described in Formula I (‘Compound X’), fortherapeutic or prophylactic use in humans.

-   -   Cream: 2-12% Active ingredients (Compound X)        -   and 88-98% Inactive ingredients

Inactive Ingredients % (w/w) Water 64.90 Hexadecan-1-ol (C₁₆H₃₄O, Cetylalcohol) 3.0 Octadecan-1-ol (C₁₈H₃₈O, Stearyl alcohol) 8.5 Isopropylmyristate (C₁₇H₃₄O₂) 1.0 Glycerine 0.2 Propylene glycol 20.0 Polysorbate20 (TWEEN 20) 2.0 Isopropyl palmitate 0.2 Benzole Acid 0.2 Total forinactive ingredients 100.00The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound of formula I:

wherein: each R¹ is independently H, (C₁-C₆)alkyl, (C₃-C₇)carbocycle orR_(a)C(═O); or the two R¹ groups together form a —(C₃-C₈)alkyl-group, a—(C₂-C₆)alkyl-Y—(C₂-C₆)alkyl-group or a—(C₁-C₆)alkyl-Y′—(C₁-C₆)alkyl-group; or the dashed bonds labeled “a” areabsent and the dashed bonds labeled “b” are double bonds; or all thedashed bonds are single bonds; R² is H, (C₁-C₆)alkyl or aryl, whereinaryl is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)Z¹ groups; R³ is H, (C₁-C₆)alkyl or aryl, wherein aryl is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; R⁴ ishydroxy, carboxy, (C₁-C₆)alkoxycarbonyl, —OPO₃H₂, —OR_(c), or—NR_(d)R_(e); and R⁵ is H; or R⁴ and R⁵ taken together are oxo; Y is O,S, NH, P, P(═O) or POH; Y′ is Si(R_(b))₂ or —Si(R_(b))₂—O—Si(R_(b))₂—;each R_(a) is independently (C₁-C₆)alkyl, (C₃-C₇)carbocycle or aryl,wherein aryl is optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups; each R_(b) is independently (C₁-C₆)alkyl,(C₃-C₇)carbocycle or aryl, wherein aryl is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; R_(c) is R_(f) or a C₁-C₂₀saturated or C₂-C₂₀ unsaturated carbon chain that is optionallysubstituted with one or more groups independently selected from oxo(═O), hydroxy, mercapto, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, and aryl, wherein aryl isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups; R_(d) is H, (C₁-C₆)alkyl, or (C₁-C₆)alkanoyl; R_(e) is H or aC₁-C₂₀ saturated or C₂-C₂₀ unsaturated carbon chain that is optionallysubstituted with one or more groups independently selected from oxo(═O), hydroxy, mercapto, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, and aryl, wherein aryl isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups; each R_(f) is:

each Z¹ is independently selected from (C₁-C₆)alkyl, halogen, —CN,—OR_(n1), —NR_(q1)R_(r1), —NR_(n1)COR_(p1), —NR_(n1)CO₂R_(p1), NO₂,—C(O)R_(n1), —C(O)OR_(n1) and —C(O)NR_(q1)R_(r1), wherein any(C₁-C₆)alkyl of Z¹ is optionally substituted with one or more (e.g. 1,2, 3, 4, 5 or 6) halogen; each R_(n1) is independently selected from Hand (C₁-C₆)alkyl, wherein any (C₁-C₆)alkyl of R_(n1) is optionallysubstituted with one or more (e.g. 1, 2, 3, 4, 5 or 6) halogen; eachR_(p1) is independently (C₁-C₆)alkyl; and R_(q1) and R_(r1) are eachindependently selected from H and (C₁-C₆)alkyl or R_(q1) and R_(r1)together with the nitrogen to which they are attached form a piperidine,pyrrolidine, morpholine, azetidine, thiomorpholine, piperazine or4-methylpiperazine; or a salt thereof.
 2. The compound of claim 1 whichis a compound of formula Ia:

or a salt thereof.
 3. The compound of claim 1 which is a compound offormula Ib:

or a salt thereof.
 4. The compound of claim 1 wherein each R¹ isindependently H or (C₁-C₆)alkyl.
 5. The compound of claim 1 wherein Y isNH.
 6. The compound of claim 1 wherein each R¹ is H.
 7. The compound ofclaim 1 wherein R² and R³ are each independently (C₁-C₆)alkyl.
 8. Thecompound of claim 1 wherein R⁴ is hydroxyl.
 9. The compound of claim 1wherein R⁴ is carboxy.
 10. The compound of claim 1 wherein R⁴ is(C₁-C₆)alkoxycarbonyl.
 11. The compound of claim 1 wherein R⁴ is OPO₃H₂.12. The compound of claim 1 wherein R⁴ is —OR_(c).
 13. The compound ofclaim 1 wherein R⁴ is —NR_(d)R_(e).
 14. The compound of claim 1 whereinR_(c) is a C₁-C₂₀ saturated or C₂-C₂₀ unsaturated alkanoyl group that isoptionally substituted with one or more groups independently selectedfrom oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, and aryl.
 15. The compound ofclaim 1 wherein R_(c) is a C₁-C₂₀ saturated or C₂-C₂₀ unsaturatedalkanoyl group that is optionally substituted with one or more groupsindependently selected from oxo (═O), hydroxy, mercapto, carboxy, andaryl, and R_(f).
 16. The compound of claim 1 wherein R_(c) is R_(f). 17.The compound of claim 1 wherein R_(c) is butanoyl, hexadecanoyl,octadecanoyl, benzoyl, 3-phenylprop-2-enoyl, or3-(4-methoxyphenyl)prop-2-enoyl.
 18. The compound of claim 1 whereinR_(e) is H or a C₁-C₂₀ saturated or C₂-C₂₀ unsaturated alkanoyl groupthat is optionally substituted with one or more groups independentlyselected from oxo (═O), hydroxy, mercapto, (C₁-C₆)alkoxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, NR_(d)R_(e), carboxy, andaryl.
 19. The compound of claim 1 wherein R_(e) is a C₁-C₂₀ saturated orC₂-C₂₀ unsaturated alkanoyl group that is optionally substituted withone or more groups independently selected from oxo (═O), hydroxy,mercapto, carboxy, and aryl, and R_(f).
 20. The compound of claim 1wherein R_(e) is butanoyl, hexadecanoyl, octadecanoyl, benzoyl,3-phenylprop-2-enoyl, or 3-(4-methoxyphenyl)prop-2-enoyl.
 21. Thecompound of claim 1 which is selected from:

and salts thereof.
 22. The compound of claim 1 which is selected from:

and salts thereof.
 23. The compound of claim 22 which is a salt withN,N-dimethylaminoethanol or glucosamine.
 24. A composition comprising acompound of claim 1 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier. 25-26. (canceled)
 27. A method ofprotecting mammal skin from photo-damage comprising contacting the skinwith one or more compounds as described in claim 1 or pharmaceuticallyacceptable salts thereof.
 28. A method of protecting DNA in mammal skinfrom photo-damage comprising contacting the skin with one or morecompounds as described in claim 1 or pharmaceutically acceptable saltsthereof.
 29. A method of repairing photo-damage in a mammal skincomprising contacting the skin with one or more compounds as describedin claim 1 or pharmaceutically acceptable salts thereof.
 30. A method ofstimulating DNA repair in a mammal skin comprising contacting the skinwith one or more compounds as described in claim 1 or pharmaceuticallyacceptable salts thereof.
 31. A method of preventing skin cancer inmammal or reducing the likelihood of contracting skin cancer in a mammalcomprising contacting the skin with one or more compounds as describedin claim 1 or pharmaceutically acceptable salts thereof.
 32. (canceled)33. A method of reversing the signs of skin aging or preventing skinwrinkles in a mammal comprising contacting the skin with one or morecompounds as described in claim 1 or pharmaceutically acceptable saltsthereof.
 34. A method of treating xeroderma pigmentosum in a mammalcomprising contacting the skin with one or more compounds as describedin claim 1 or pharmaceutically acceptable salts thereof. 35-36.(canceled)
 37. A method of treating or preventing ionizing radiationdamage in a mammal comprising treating the mammal with one or morecompounds as described claim 1 or pharmaceutically acceptable saltsthereof. 38-49. (canceled)
 50. The compound of claim 1 which is not: